The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis

Jin Xu*, Nan Zhong, Haoyong Wang, Joshua E. Elias, Christina Y. Kim, Irina Woldman, Christian Pifl, Steven P. Gygi, Changiz Geula, Bruce A. Yankner

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

Mutations in the DJ-1 gene cause early-onset autosomal recessive Parkinson's disease (PD), although the role of DJ-1 in the degeneration of dopaminergic neurons is unresolved. Here we show that the major interacting-proteins with DJ-1 in dopaminergic neuronal cells are the nuclear proteins p54nrb and pyrimidine tract-binding protein-associated splicing factor (PSF), two multifunctional regulators of transcription and RNA metabolism. PD-associated DJ-1 mutants exhibit decreased nuclear distribution and increased mitochondrial localization, resulting in diminished co-localization with co-activator p54nrb and repressor PSF. Unlike pathogenic DJ-1 mutants, wild-type DJ-1 acts to inhibit the transcriptional silencing activity of the PSF. In addition, the transcriptional silencer PSF induces neuronal apoptosis, which can be reversed by wild-type DJ-1 but to a lesser extent by PD-associated DJ-1 mutants. DJ-1-specific small interfering RNA sensitizes cells to PSF-induced apoptosis. Both DJ-1 and p54nrb block oxidative stress and mutant α-synuclein-induced cell death. Thus, DJ-1 is a neuroprotective transcriptional co-activator that may act in concert with p54nrb and PSF to regulate the expression of a neuroprotective genetic program. Mutations that impair the transcriptional co-activator function of DJ-1 render dopaminergic neurons vulnerable to apoptosis and may contribute to the pathogenesis of PD.

Original languageEnglish (US)
Pages (from-to)1231-1241
Number of pages11
JournalHuman molecular genetics
Volume14
Issue number9
DOIs
StatePublished - May 1 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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